Protected guanidines having an important role in the synthesis of peptides having arginine residues. Various mimics to arginine have been used as peptide building blocks. From a synthetical and commercial point of view, arginine-mimics having a simplified structure compared to arginine are of particular interest. Perhaps the most attractive structural simplification of arginine is replacing the carboxylic group in arginine with a hydrogen giving a non-chiral molecule. The most important arginine derivatives in this context are noragmatine (N-(3-aminopropyl)-guanidine) and agmatine (N-(4-aminobutyl)-guanidine). More generally, .omega.-aminoalkyl guanidines of varying chain length are interesting as peptide building blocks, particularly as a substitute for an arginine terminus in a peptide.
Previously known examples of applications of peptide building blocks, of the general type --NH--C(.dbd.NH)--NH--[CH.sub.2 ].sub.n --NH-- are, see for example: U.S. Pat. No. 4,387,049 disclosing example where n=3 (noragmatine), and U.S. Pat. No. 4,346,078 disclosing example where n=4 (agmatine).
A free guanidino group [--NH--C(.dbd.NH)--NH.sub.2 ] provides synthetic complications and to be synthetically useful the building block requires a protective group (PG) which may be removed from the guanidino group at a desired stage of the synthesis. EQU PG--NH--C(.dbd.NH)--NH--[CH.sub.2 ].sub.n --NH.sub.2
Frequently used protective groups for the guanidino group in arginine are for example alkoxycarbonyls such as t-butoxycarbonyl (Boc) and aralkoxycarbonyls such as benzyloxycarbonyl (Z), See for example: Wunsch E. "Methoden der Organischen Chemie (Houben Weyl), Syntheses von Peptiden", 1974, 15/1,506 ff. and Rzeszotarska Masiukiewicz Org. Prep. Proc. Int. 1988, 20, 427 ff. The expressions Boc and Z are used in the following description as abbreviates for t-butoxycarbonyl and benzyloxycarbonyl, respectively.
Guanidino protected .omega.-aminoalkyl guanidines, PG.sub.2 --NH--C(.dbd.NH)--NH--[CH.sub.2 ].sub.n--NH.sub.2 (3), are generally prepared starting from a mono-protected diaminoalkane (1) in which the free amino group is reacted with an electrophilic guanylation reagent, HN.dbd.C(L)--NH.sub.2 where L is a leaving group, commonly used in guanidine syntheses. The reaction produces an amino protected .omega.-aminoalkyl guanidine (2) which after protection of the guanidino group with a second protective group (PG.sub.2) and deprotection of the amino protective group (PG.sub.1) gives the desired PG.sub.2 --NH--C(.dbd.NH)--NH--[CH.sub.2 ].sub.n --NH.sub.2 (3). In this method the protective groups have to be orthogonal. Examples of guanylation reagents that may be used are L=OMe, SMe, pyrazol-1-yl, 3,5-dimethyl-pyrazo-1-yl, and SO.sub.3 H. Recent developments have proposed introduction of the second protective group, PG.sub.2, in the guanylation reagent. Such a method simplifies the linear synthesis and shortens it with one step, (1.fwdarw.3), see scheme 1. ##STR1##
Previously proposed guanylation reagents [PG.sub.2 --NH--C(L).dbd.NH], carrying a protective group useful in guanidine syntheses, i.e. used to create a guanidino group, are disclosed in the following list: for L/PG.sub.2 :
3,5-dimethyl-pyrazo-1-yl/NO.sub.2 and 3,5-dimethyl-pyrazo-1-yl/tosyl; MeS/NO.sub.2 ; PA1 MeS/tosyl (See for example: Int. J. Peptide Res. 1991, 37, 425); PA1 MeO/benzyloxycarbonyl (See for example: DE 3222342 A1); PA1 MeS/benzyloxycarbonyl (See for example GB 2085444 A.
The mono protected diamine is generally prepared from the corresponding amino alcohol according to the four-steps protocol shown in scheme 2, (See for example Mattingly Synthesis 1990, 366). ##STR2##
Consequently, methods previously known in the art totally require 6 to 7 synthetic steps in order to prepare a guanidino protected .omega.-aminoalkyl guanidine, PG.sub.2 --NH--C(.dbd.NH)--NH--[CH.sub.2 ].sub.n --NH.sub.2 (3). See scheme 1 in combination with scheme 2. Such compounds, where the protective group (PG) is a alkoxycarbonyl or aralkoxycarbonyl, such as for example t-butoxycarbonyl or benzyloxycarbonyl, can now be produced more efficiently in the one step synthesis using the process of the present invention.